1. Field of the Invention
This invention relates to delivery of polycyclic, aromatic, antioxidant or anti-inflammatory compounds to a biological organism. In particular, the invention relates to liposomes and formulations of drugs, nutrients and other compounds into liposomes to improve or effect delivery of such beneficial compounds to cells and tissues in an organism. Specifically, the invention provides such liposome compositions of polycyclic, aromatic, antioxidant or anti-inflammatory compounds in formulations advantageously administered orally to an animal.
2. Background of the Related Art
Cardiovascular disease (including atherosclerosis, myocardial infarction, ischemia, stroke, pulmonary embolism and other thrombotic diseases) and cancer are major causes of mortality in the U.S., being responsible for up to two-thirds of all deaths per annum. Despite advances in preventative medicine, diet, exercise, diagnostics and therapeutic approaches that have increased the average lifespan of U.S. citizens and reduced the number of premature deaths, these diseases ultimately are no less responsible for mortality than they were a generation ago.
Certain plant-derived compounds have been recognized as being beneficial both as anticancer and anticardiovascular disease agents. This class of compounds is generally recognized to include polycyclic, aromatic compounds having antioxidant or anti-inflammatory activity, and include the flavonoids (such as flavone, quercetin and chrysin) and derivatives of stilbenes, such as resveratrol. The effects of these compounds as anticancer and anticardiovascular disease agents are both anecdotal and subject to modern scientific scrutiny. One example of anecdotal evidence for the beneficial effects of these compounds is with regard to what has been termed xe2x80x9cFrench paradox.xe2x80x9d The paradox is that although the French diet is high in nutrients (such as cholesterol and saturated fats) that have been associated with a risk of arteriosclerosis and cardiovascular disease, French citizens have less cardiovascular disease than their counterparts in other Western countries. The purported reason for this result is that French citizens also consume more red wine that other Western country citizens, and red wine is high (5-50 parts per million) in one polycyclic, aromatic antioxidant compound, resveratrol (Siemann and Creasy, 1992, Am. J. Enol. Vitic. 43: 49-52; Kopp et al., 1998, Eur. J. Endocrinol. 138: 619-620). Resveratrol is also a component of a traditional oriental medicine, Ko-jo-kon, used to treat ailments of the heart, blood vessels and liver. Soleas et al., 1997, Clin. Biochem. 30: 91-113.
Resveratrol is found in red wine due to its presence in grape skins and is thought to be a phytoalexin that provides protection against fungi. Celotti et al., 1996, J. Chromatog. 730: 47-52. It is also found (at much lower concentrations) in eucalyptus, spruce, lily, mulberry and peanuts.
Resveratrol has also been the subject of several scientific studies. The Copenhagen Heart Study (1995) showed that the relative risk of mortality from coronary artery disease was reduced by 20% when red wine was consumed once a month, by 30% when red wine was consumed once or twice weekly, and by 40% when red wine was consumed 3-5 times per week. Other researchers investigated the physiologic basis for these results. Pendurthi et al. (1999) showed that resveratrol, dose-dependently, inhibited transcription and expression of tissue factor in endothelial cells. Arterioscherosis Thrombosis and Vascular Biol. 19: 419-426. Resveratrol has been shown to have antioxidant (Chanvitayapongs et al., 1997, Neuroreport 8: 1499-1502; Belguendouz et al., 1998, Biochem. Pharmacol. 55: 811-816; Frankel et al., 1993, Lancet 341: 1103-1104), platelet aggregation inhibiting (Bertelli et al., 1996, Drugs Exp. Clin. Res. 22: 61-63; Rotondo et al., 1998, Brit. J. Pharmacol. 123: 1691-1699) and vasodilating (Chen et al., 1996, Gen. Pharm. 27: 363-366) properties. Resveratrol has also been shown to have cancer chemopreventative properties (Jang et al., 1997, Science 275: 218-220), putatively by inhibiting COX-1 and COX-2 and tumor promotion thereby (Subbaramaiah et al., J. Biol. Chem. 273: 21875-21882; Clement et al., 1998, Blood 92: 996-1002; Fontecave et al., 1998, FEBS Lett. 421: 277-279).
As a consequence, the World Health Organization estimates that coronary artery disease could be reduced by up to 40% if resveratrol or resveratrol-containing foods were consumed in proper amounts.
Chrysin (5,7-dihydroxyflavone) is a naturally-occurring flavone found in passion flower (Passiflora coerulea) extracts. Chrysin has activity as an anxiolytic agent (Wolfman et al., 1994, Pharmacol. Biochem. Behav. 47: 1-4; Paladini et al., 1999, J. Pharm. Pharmacol. 51: 519-526), an anticonvulsant (Medina et al., 1990, Biochem. Pharmacol. 40: 2227-31), an agent that reverses P-glycoprotein mediated multidrug resistance in human cancer cells (Barron et al., 2nd International Electronic Conference on Synthetic Organic Chemistry (ECSOC-2), Sep. 1-20, 1998, www.mdpi.org/ecsoc), and as a protein kinase inhibitor (Hagiwara et al., 1988, Biochem. Pharmacol. 37: 2987-2992). Myocardial infarction risk in elderly men is decreased by chrysin (Hertog et al., 1993, Lancet 342: 1007-1011). Chrysin is believed to act by inhibiting aromatase, an enzyme responsible, inter alia, for converting testosterone to estrogen.
Quercetin (3,3xe2x80x2, 4xe2x80x2, 5,7-pentahydroxyflavone) is a natural substance found in apples, onions, tea and red wine (like resveratrol, it is derived from grape skins). Quercetin has been shown to be an antioxidant. Cai et al., 1999, Free Radical Biol. Med. 27: 822-829. Quercetin has been shown to be an efficacious agent for preventing and treating prostate cancer by workers at the Mayo Clinic. Xing et al., American Association for Cancer Research, 26th Annual Meeting, Mar. 26, 2001. Prostate cancer is the second leading cause of death in men, with 31,500 fatalities and 200,000 diagnoses per year. Quercetin is currently in therapeutic use for treating inflammatory diseases and disorders.
A major goal in the pharmacological arts has been the development of reagents and methods that reduce the necessity of administering therapeutic compounds, drugs and other agents invasively (i.e., such as by injection). Most preferably, it has been a consistent goal in the art to develop therapeutic compounds, drugs and agents and formulations thereof that permit oral administration (see, for example U.S. Pat. No. 4,963,526 to Ecanow issued Oct. 16, 1990), although other reduced-invasiveness formulations such as suppositories have also been developed. Among the various routes of drug administration, the oral intake of drugs is undoubtedly preferred because of its versatility, safety and patient comfort.
In addition, it has been a goal in the nutritional arts to develop preparations that increase transit of certain nutrients through the gastrointestinal tract to increase uptake and delivery of such nutrients into the bloodstream. In particular, such preparations have been developed to permit chemically-labile nutrients (such as vitamins and other sensitive compounds) to pass through the chemically-hostile environment of the stomach for absorption in the intestines (see, for example, U.S. Pat. No. 5,958,450 to Tashiro issued Sep. 28, 1999). Preparations having enhanced intestinal uptake have also been deemed desirable.
One approach known in the prior art for improving efficiency of delivery of therapeutic compounds, drugs and other agents has been to envelop such compounds in a specialized lipid structure termed a liposome (see, for example, U.S. Pat. No. 4,744,989 to Payne et al. issued May 17, 1988). Liposomes generically comprise an enclosed lipid droplet having a core, typically an aqueous core, containing the compound. In certain embodiments, the compound is chemically conjugated to a lipid component of the liposome. In other embodiments, the compound is simply contained within the aqueous compartment inside the liposome.
Certain liposome formulations are known in the art.
U.S. Pat. No. 5,223,263, issued Jun. 29, 1993 to Hostetler et al. discloses conjugates between antiviral nucleoside analogues and polar lipids for inclusion in liposomes.
U.S. Pat. No. 5,466,468 to Schneider et al. issued Nov. 14, 1995 discloses parenterally administrable liposome formulations comprising synthetic lipids.
U.S. Pat. No. 5,484,809, issued Jan. 16, 1996 to Hostetler et al. discloses taxol and taxol derivatives conjugated to phospholipids.
U.S. Pat. No. 5,580,571, issued Dec. 3, 1996 to Hostetler et al. discloses nucleoside analogues conjugated to phospholipids.
U.S. Pat. No. 5,626,869 to Nyqvist et al. issued May 6, 1997 discloses pharmaceutical compositions wherein the pharmaceutically active compound is heparin or a fragment thereof contained in a defined lipid system comprising at least one amphiphatic and polar lipid component and at least one nonpolar lipid component.
U.S. Pat. No. 5,744,461, issued Apr. 28, 1998 to Hostetler et al. discloses nucleoside analogues conjugated to phosphonoacetic acid lipid derivatives.
U.S. Pat. No. 5,744,592, issued Apr. 28, 1998 to Hostetler et al. discloses nucleoside analogues conjugated to phospholipids.
U.S. Pat. No. 5,756,116, issued May 26, 1998 to Hostetler et al. discloses nucleoside analogues conjugated to phospholipids.
U.S. Pat. No. 5,843,509 to Calvo Salve et al. issued Dec. 1, 1998 discloses stabilization of colloidal systems through the formation of lipid-polysaccharide complexes comprising a water soluble and positively charged polysaccharide and a negatively charged-phospholipid.
International Patent Application Publication Number WO89/02733, published April 1989 to Vical discloses conjugates between antiviral nucleoside analogues and polar lipids.
European Patent Application Publication Number 0350287A2 to Vical discloses conjugates between antiviral nucleoside analogues and polar lipids.
International Patent Application Publication Number WO93/00910 to Vical discloses conjugates between antiviral nucleoside analogues and polar lipids.
Rahman et al., 1982, Life Sci. 31: 2061-71 found that liposomes which contained galactolipid as part of the lipid appeared to have a higher affinity for parenchymal cells than liposomes which lacked galactolipid.
Gregoriadis, 1995, Trends in Biotechnology 13: 527-537 reviews the progress and problems associated with using liposomes for targeted drug delivery.
Ledley, 1995, Human Gene Therapy 6: 1129-1144 reviews the use of liposomes for gene therapy.
Mickisch, 1995, World J. Urology 13: 178-185 reviews the use of liposomes for gene therapy of renal cell carcinoma.
Yang et al. 1997, J. Neurotrauma 14: 281-297 review the use of cationic liposomes for gene therapy directed to the central nervous system.
Storm and Crommelin, 1997, Hybridoma 16: 119-125 review the preliminary use of liposomes for targeting chemotherapeutic drugs to tumor sites.
Manusama et al., 1998, Semin. Surg. Oncol. 14: 232-237 report on preclinical and clinical trials of liposome-encapsulated tumor necrosis factor for cancer treatments.
Although liposomes have conventionally been administered parenterally (see, for example, U.S. Pat. No. 5,466,468), reports of oral administration of liposome-related formulations have appeared in the art.
U.S. Pat. No. 4,921,757 to Wheatley et al. issued May 1, 1990 discloses controlled release of biologically active substances, such as drugs and hormones entrapped in liposomes that are protected from the biological environment by encapsulation within semi-permeable microcapsules or a permeable polymeric matrix.
U.S. Pat. No. 5,043,165 to Radhakrishnan to Aug. 27, 1991 disclosed a liposome composition for sustained release of steroidal drugs.
U.S. Pat. No. 5,762,904 to Okada et al. issued Jun. 9, 1998 discloses oral delivery of vaccines using polymerized liposomes.
U.S. Pat. No. 5,955,451 to Lichtenberger et al. issued Sep. 21, 1999 discloses compositions comprising non-steroid anti-inflammatory drugs (NSAID""s) complexed with either zwitterionic or neutral phospholipids, or both, having reduced gastrointestinal irritating effects and enhanced antipyretic, analgesic, and anti-inflammatory activity.
Proliposomes are an alternative to conventional liposomal formulations. Proliposomes are dry, free-flowing granular products, which, on addition of water, disperse to form a multi-lamellar liposomal suspension. The stability problems associated with conventional liposomes such as aggregation, susceptibility to hydrolysis and/or oxidation are avoided by using proliposomes.
U.S. Pat. No. 5,635,206 to Ganter et al. discloses a process for preparing liposomes or proliposomes.
U.S. Pat. No. 5,595,756 to Bally et al. discloses that the bioactive agent concentration in plasma increases when a synergistic effect is induced by lowering the pH (to approximately 2-3) of the solution in which a bioactive agent is entrapped within a liposome and including in the liposomal membrane an amine-bearing lipid.
U.S. Pat. No. 6,093,406 to Alving et al. teaches liposomal derived vaccines that use a liposome and a compound that contains a net negative charge, a net positive charge (via stearylamine) or is neutral in conjunction with liposomes adsorbed to aluminum hydroxide.
Proliposomes of indomethacin were prepared using effervescent granules, which upon hydration yielded liposomes of high encapsulation efficiency and increased anti-inflammatory activity with decreased ulcerogenic index (see, for example, Katare et al., 1991, J. Microencapsulation 81: 1-7).
The proliposomal concept has been extended to administer drugs through various routes and also to the food industry wherein enzyme immobilization is essential for various food processing regimes. A typical example is the immobilization of the enzyme, chymotrypsin, in liposomes obtained from proliposomes.
There remains a need in the art for a general, inexpensive and effective means for delivering compounds such as polycyclic, aromatic, antioxidant or anti-inflammatory or anti-inflammatory compounds to an animal by oral administration. Advantageous embodiments of such delivery means are formulated to efficiently deliver such compounds to the appropriate portion of the gastrointestinal tract for efficient absorption.
The present invention is directed to an improved method for delivering polycyclic, aromatic, antioxidant or anti-inflammatory compounds to an animal by oral administration. This delivery system achieves specific delivery of such polycyclic, aromatic, antioxidant or anti-inflammatory compounds through associating the compounds with liposomes and proliposome components.
In preferred embodiments, the polycyclic, aromatic, antioxidant or anti-inflammatory compound is formulated as a proliposomal composition that can be reconstituted in vivo to provide a liposomal preparation. Preferably, the invention provides pharmaceutical compositions comprising the polycyclic, aromatic, antioxidant or anti-inflammatory compound and a lipid formulated as a proliposomal preparation. In more preferred embodiments, the pharmaceutical compositions of the invention are formulated for oral administration. Most preferably, the pharmaceutical compositions of the invention formulated for oral administration comprise an enteric coating sufficient to prevent dissolution of the composition in the stomach of an animal. In alternative embodiments, the pharmaceutical compositions also comprise a protective coating between the enteric coating and the core of the composition comprising the proliposomal components thereof. Additional advantageous components of said orally-administrable pharmaceutical compositions further comprise the pharmaceutical compositions as will be understood by those with skill in the art.
Specific preferred embodiments of the present invention will become evident from the following more detailed description of certain preferred embodiments and the claims.